PROJECT SUMMARY Sulfur mustard is well known to affect the respiratory tract in a dose-dependent fashion, resulting in time- dependent `phases' of lung injury caused by differing underlying pathogenesis. The hallmark of acute injury is airway fibrin cast formation. This phase is followed by infection within the pulmonary tract, with the potential for progression to chronic pulmonary fibrosis of airways, as in bronchiolitis obliterans (BO) and lung parenchymal fibrosis (PF), occurring months to years after acute injury in survivors. Such chronic fibrotic lung disease conditions are estimated to occur in as many as 50-75% of SM exposed individuals, causing significant late- onset morbidity and mortality. Current treatment focuses on providing supportive measures, with no known therapy to prevent, stop progression of, or revere airway or parenchymal lung fibrosis development. Recent data in our laboratory has indicated that acute mortality due to airway cast obstruction can be eliminated with the employment of airway-delivered tissue plasminogen activator (tPA), even when started 6-24 hours after SM inhalation. Unfortunately, survivors of the acute phase of SM inhalation injury, even if treated with tPA, can still develop subacute pulmonary infections and subsequent chronic lung fibrosis in our rat model, contributing significantly to latent morbidity and mortality. More recently, we found that the anti-fibrotic drug pirfenidone, when started 10 days after SM inhalation, decreased pulmonary function abnormalities and diminished the elevated pro-fibrotic TGF-? and PDGF signaling associated with PF and BO after SM exposure. In this project, we hypothesize that the anti-fibrotic drugs pirfenidone and/or nintedanib will decrease PF and/or BO pathology, biochemical changes, and lung physiologic dysfunction, including gas exchange and lung function tests. Additionally, we hypothesize that infection may play a key role in lung fibrosis development, and treatment with targeted antibiotics may be beneficial in alleviation of lung fibrosis. These approaches should provide effective therapies for treatment of SM inhalation survivors. To test their potential as anti-fibrotic agents, pirfenidone and nintedanib will be given orally immediately after or 10 days after SM exposure. We will also evaluate possible underlying mechanisms by which the therapies may exert their efficacy in this model. This proposal will develop practical agent(s) for treatment of lung fibrosis after SM inhalation.